Mutation of the c-Cbl TKB Domain Binding Site on the Met Receptor Tyrosine Kinase Converts It into a Transforming Protein

P. Peschard, T.M. Fournier, L. Lamorte, M.A. Naujokas, H. Band, Wallace Langdon, M. Park

Research output: Contribution to journalArticle

339 Citations (Scopus)

Abstract

The c-CbI protooncogene is a negative regulator for several receptor tyrosine kinases (RTKs) through its ability to promote their polyubiquitination. Hence, uncoupling c-CbI from RTKs may lead to their deregulation. In testing this, we show that c-CbI promotes ubiquitination of the Met RTK. This requires the c-Cbl tyrosine kinase binding (TKB) domain and a juxtamembrane tyrosine residue on Met. This tyrosine provides a direct binding site for the c-CbI TKB domain, and is absent in the rearranged oncogenic Tpr-Met variant. A Met receptor, where the juxtamembrane tyrosine is replaced by phenylalanine, is not ubiquitinated and has transforming activity in fibroblast and epithelial cells. We propose the uncoupling of c-CbI from RTKs as a mechanism contributing to their oncogenic activation.
Original languageEnglish
Pages (from-to)995-1004
JournalMolecular Cell
Volume8
Issue numberN/A
DOIs
Publication statusPublished - 2001

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